7-keto-4b-methyl-1,2,3,4,4a,4b,5,6,7,9,10,10a-dodecahydrophenanthrene-1,4-diol and its preparation



Patented Nov. 11, 1952 V UNITED STATES PATENT OFFICE 7 -KETO-4b-METHYL- 1,2,3,4,4a,4b,5,6,7,9,10,10a-

DODECAHYDROPHENANTHRENE-1,4 DIOL AND ITS PREPARATION Lewis H. Sarett, Princeton, and Roger E. Beyler, Metuchen, N. J., assignors to Merck & 00., Inc., Rahway, N. J., a corporation of New Jersey No Drawing. Application May 24, 1951, Serial No. 228,126

6 Claims. (Cl. 260-586) I 1 2 This invention is concerned generally with producing said 7-keto-4b-methyl-1,2,3,4,4a,4b,5,- polyhydrophenanthrene compounds and with 6,7,9,10,10a-dodecahydrophenanthrene 1,4 diol processes for preparing them. More particular- (Compound 2). 1y, it relates to the novel compound 7-keto-4b- This reaction may be chemically represented methyl-1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydro- 5 as follows:

I I CH:

Ha H H2 i J no CH1 CH 6 t 0113 E H-OH o E HOH C CH methyl vinyl H1O CE I I O=C\ /CH1 7 ketone O=C\ H: o 0 o H: H H:

- Compound'l Compound 2 phenanthrene-IA-dioI, and with the novel proc- The methyl-G-keto-perhydronaphthaleneess of preparing this compound starting with lA-diol, employed as a starting material in this 5-methyl-6keto-perhydronaphthalene-1,4-dio1. n v l pr c s a n w mp u d w h ay be The new compound, 7-keto-4b-methyl-1,2,3,4,- prepared according to the following procedure 4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene- B-ethoxy-propionaldehyde is reacted with ethyl 1,4-diol, may be chemically represented as folmagnesium bromide to produce l-ethoxy-3-hylows: droxy-pentane which is reacted with chromic CH3 acid thereby oxidizing the hydroxy substituent to form l-ethoxy-B-keto-pentane; the latter com- E" pound is treated with ethyl orthoformate and ethanol in the presence of hydrogen chloride to produce 1,3,3-triethoxy-pentane which, upon re- HOH action with hot potassium bisulfate, is converted g to 3-ethoXy-1,3-pentadiene. The 3-ethoxy-1,3-

,, i pentadiene is then reacted with benzoquinone in )K accordance wtih the Diels-Alder condensation g g procedure to produce 5-methyl-6-ethoxy-1,4,4a,-

5,8,8a-hexahydronapthalene-1,4-dione which is This compound possesses the ABC ring system then reacted with hydrogen in the presence of characteristic of certain members of the steroid Raney nickel catalyst to form 5-methyl-6-ethgroup of compounds, and also possesses the anoXy-1,2,3,4,4a,5,8,8a-octahydronaphthalene 1,4- gular ib-methyl grouping (corresponding to posidione; thelatter compound is reacted with lithtion 10 according to conventional steroid nomen- 4O ium aluminum hydride to form the correspondclature) together with the proper functional subing diol, 5-methyl-6-ethoxy-1,2,3,4,4a,5,8,8a-ocstitution in ring C characteristic of adrenal hortahydronapthalene-1,4-diol which is reacted with mones such as cortisone, Compound F and cora hydrolyzing agent to produce 5-methyl-6-ketoticosterone. 7-keto-4b-methyl-1,2,3,4,4a,4b,5,6,- perhydronaphthalene-1,4-dio1. The reactions in- 7,9,10,l0a-dodecahydrophenanthrene-1,4-dio1 is 5 dicated above are described in detail in a cocapable of further elaboration to a steroid mempending application of one of the present appliber and is of value in the total synthesis of steroid cants, Serial No. 216,109, filed March 16, 1951, hormones. In accordance with the present invention, the

The 7-keto-4hmethyl-1,2,3,4,4a,4b,5,6,7,9,10,- 5-methyl-6-keto-perhydronaphthalene 1,4 diol l0a-dodecahydrophenanthrene-1,4-diol, subject is brought into intimate contact, in an alkaline of the present invention, can be prepared by reaction medium, with methyl vinyl ketone to bringing into intimate contact, in the presence produce 7-keto-4b-methyl-1,2,3,4,4a,4b,5,6,7,9,l0,-

of an alkaline condensation agent, 5methyl--6- 10a-dodecahydrophenanthrene-1,4-diol. If del h drgnaphthalene-1,4-diol (Compound 1 sired, methyl vinyl ketone per so can be incorpohereinbelowi and methyl vinyl-l zetone thereby rated in the reaction medium. However, it is alternatively possible to bring together, in the alkaline medium, the -methyl-6-keto-perhydronaphthalene-1,4-diol and a methyl fi-substitutedethyl ketone, compound characterized as being decomposed by alkaline media with the formation of methyl vinyl ketone. Amongst the methyl fl-substituted-ethyl ketone compounds which we ordinarily utilize, in the alkaline medium, for generating methyl vinyl ketone, in situ, are those which may be chemically represented by the following structural formula: CHsCOCHzCHzZ, wherein the radical Z may be R2N, ;RS, RSO, RSO;, RO or X, the radical R being an alkyl or aryl substituent, and Xbeing a halo radical. We prefer to utilize the tertiary amines, CHKCOCHECHZNRZ, wherein R has the significance hereinabove defined, and quaternary salts thereof, and particularly the N-(3-keto-buty1) N,N,N-trialkylammonium halides such as N-(3- keto butyl) N,N-diethyl-N-methyl ammonium iodide, and the like.

As set forth hereinabove the processis carried out in the presence of an alkaline condensation agent which catalyzes the reaction. Any strong base can be utilized, for example an alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide, and the like, a quaternary ammonium hydroxide such as Triton B (benzyl trimethyl ammonium hydroxide), choline, and the like, an alkali metal amide such as sodamide, or'ametalorganic base such as an alkali; metal alcoholate, and the like. The'proportion'of base utilized is not criticalsince ,the reactionhas been found to proceed normally utilizing an amount of alkaline condensation agent varying from one-tenth "of an equivalent to four or more equivalents based on the 5 niethyl-6-keto-perhydronaphthalene- 1,4-diol. V

We ordinarily'utilize, as the medium for the reaction, a' polar liquid, for example, water, a lower aliphatic alcohol such as methanol, ethanol, isopropanol, andthe like, an ether such as diethyl ether, tetrahydrofuran, and the like, or a mixture of two or morefmiscible' polar liquids. The quantity of polar liquid utilized 'has'no effect on whether or not the'reaction' will go, although we prefer to utilize an amount of solvent equal to about ten times the weight of the reactants.

As set forth hereinabove, the methyl vinyl ketone can be provided in the reaction medium either by adding "methylvinyl ketone per se, or by adding a methylfi-substituted-ethyl ketone compound, such 'as diethyl (3-keto butyl) methyl-ammonium iodide, characterized as being decomposed'by alkaline media with the formation of methyl vinyl ketone. The relative amount of methyl vinyl ketone or methyl ,B-substitutedethyl ketone compound is likewise not critical since the condensation proceeds satisfactorily utilizing an amount of one of these compounds ranging from one equivalent based on the 5- methyl-6-keto-perhydronaphthalene-1,4diol to four equivalents ormore. In carrying out the reaction, the 5-methyl-fi-keto-perhydronaphthalene-l,4-diol, the polar liquid, the alkaline condensation agent, and either methyl vinyl ketone or methyl B-substituted ethyl ketone compound, are placed together, and the resulting mixture is heated for a period ranging from approximately one-half to twenty-four hours.

The 7-keto -'4b methyl-1,2,3,4,4a,4b,5,6,7,9,10, 10a-dodecahydrophenanthrene l,4-diol thus produced is conveniently recovered from the reaction mixture by acidifying the mixture with an aqueous solution of a mineral acid, and extracting heated under reflux for several minutes.

the aqueous acidic reaction mixture with a waterimmiscible organic solvent whereby the 7-ketoib-methyl-l,2,3,4,4a,4l1,5,6,7,9,10,10a dodecahydrophenanthrene-1,4-diol is transferred to the non-aqueous layer, while leaving in the aqueous layer the inorganic constituents and Water-soluble amine by-products. The 7-keto-4b-methyll,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene -lA-diol isrecovered from the non-aqueous extract by evaporating the solvent, and can be purified, if desired, by conventional means.

The following examples illustrate methods of carrying out'the-present invention, but it is to be understood that these examples are given for purposes of illustration and not of limitation.

Example 1 aqueous solution of Triton B (0.00575 mole) and 1 cc. of an aqueous solution of methyl vinyl ketone (0.012 'mole) were mixed together, and the resulting mixturewas heated under reflux for a period of'approxim'ately two hours. At the end of this period, 10 cc. of water were added to the mixture, and the resulting mixture was The ethanol was evaporated from the reaction mixture, and the normality of the residual aqueous solution was adjusted to about 1 by the addition of hydrochloric acid. The acidified solution was heated on a steam bath for a period of about five to ten minutes, cooled and extracted with chloroform. The chloroform extract was then evaporated to dryness to produce crude 7-keto-4bmethyl-1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene 1,4 diol. This compound was purified by reorystallization from ethanol to give substantially pure 7-keto-4b-methy1-1,2,3,4,4a,4b, 5,6,7,9,10,10a-dodecahydrophenanthrene-1,4-diol; M. P; 246 C. p

Example 2 Fifteen and two-tenths grams of S-methyl- 6 keto perhydronaphthalene 1,4 diol (0.0767 mole), cc. of absolute ethanol, 5 cc. of a 40% aqueous solution of Triton B (0.012 mole), and 13 cc. of an 85%aqueous solution of methyl vinyl ketone (0.158 mole) were mixed together, and the mixture was heated under reflux for a period of approximately two hours. At the end of this period, one-half of the ethanorwas evaporated from the reaction mixture,'and 50 cc. of water was added to the residual solution. The resulting aqueous solution was then heated under reflux for a period of approximately five to ten minutes, at the end of which time the remainder of the ethanol was evaporated. The normality of the residual aqueous'solution was adjusted to about 1 by the-addition of hydrochloric acid. The acidified scluti on w asheated-on a steam bath for a period of about -five toten minutes, cooled, and "extracted With'chlorofbrm. The chloroform extract was evaporated to dryness, and the residual materialwa's"purifiecl'by recrystallization from ethanol to give" substantially pure '7-keto-4b-methyl-1,2,3,4,4a,4b,5,6,7,9, 10,10a-dodecahydrophenanthrene-1,4-dioli M. P.

Example 3 One gram of 5-methyl-6keto=perhydronaphthalene-1,4-diol (0.0 Q505'mole) 9; cc.'of absolute tetrahydrofuran, 0.1687 g: of Triton" B (0.001 mole) and 2.879 g. of methyl vinyl ketone (0.041 mole) were mixed together, and the mixture was l I 511'; heated under reflux infa'n atmosphere of nitrogen for a period of approximately one hourl At the end of this period, 90a. of water was added to the reaction mixture, and the tetrahydrofuran was evaporated from, the aqueous mixture thus obtained. The normality of the resulting aqueous solution was adjusted to about 1 by the addition of hydrochloric acid. The acidified solution was heated on a steam bath for a period of about ten minutes, cooled and extracted with chloroform. The chloroform extract was evap- 7 cc. of water, 0.14 g. of an 85% aqueoussolu- I tion of potassium hydroxide (0.00214 mole), 0.6 cc. of an 85% aqueous solution of methyl vinyl ketone (0.0071 mole), and 0.8 cc. of a 40% aqueous solution of Triton B (0.0007 mole) were mixed together; and the'mixture was heated under reflux for a period of approximately one hour. At the end of this period, the normality of the reaction solution was adjusted to approximately 1 by the addition of hydrochloric acid, and the acidified solution was heated on a steam bath for a period of about fifteen minutes. The resulting solution was cooled, and extracted with chloroform. The chloroform extract was evaporated to dryness, and the residual material was purified by recrystallization from ethanol to give substantially pure 7-keto-4bmethyl 1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene-L4-diol; M. P. 246 C.

Example 5 addition f hydrochloric acid, the acidified solution was heated on a steam bath for a period of about fifteen minutes, and the resulting solution was cooled and extracted with chloroform. The chloroform extract was evaporated to dryness, and the residual material was purified by recrystallization from ethanol to give substantially pure 7-keto-4b-methyl-l,2,3,4,4a,4b,5,6,7,- 9,10,10a dodecahydrophenanthrene 1,4 diol; M. P. 246 C.

Example One gram of 5-methyl-6-keto-perhydronaphthalene-1,4-diol (0.00505 mole), 12 cc. of water, 1.33 g. of an 85% aqueous solution of potassium hydroxide (0.0202 mole), and 3.9817 g. of diethyl-(3-keto -butyl) -me thyl-ammonium iodide (0.01398 mole) were mixed together, and the mixture was heated under reflux for a period of approximately two hours. At the end of this period, the normality of the reaction solution was adjusted to approximately 1 by the addition "of hydrochloric acid, the acidified solution was heated on a steam bath fora period of five minutes and the resulting mixture was cooled" and extracted with chloroform. The chloroform extract was evaporated to dryness, and the residual material-was purified by recrystallization from ethanol to give substantially pure 7-keto- 4b methyl -1,2,3,4,4a,4b,5,6,7,9,10.1011 dodecahydrophenanthrene 1,4-diol; M. P. 246 C.

Example 7 Five-tenths of a gram of 5-methy1-6-ketoperhydronaphthalene -1,4-diol (0.00252 mole), 0.784 g. of diethyl-(3-keto-butyl)-methyl-ammonium iodide (0.00274 mole), 3 cc. of absolute ethanol, 3 cc. of water, and 0.495 g. of an aqueous solution of potassium hydroxide (0.0075 mole) were mixed together, and the resulting mixture was heated under reflux for a period of one hour. At the end of this period, the ethanol was evaporated from the reaction mixture, and the normality of the resulting solution was adjusted to. approximately 1 by the addition of Example 8 Five cubic centimeters of water, 0.992 g. of 5-methyl-6-keto-perhydronaphthalene-1,4 diol (0.0050 mole), 0.7 cc. of a 40% aqueous solution of Triton B (0.001678 mole) and 0.9 cc. of an 85% aqueous solution of methyl vinyl ketone (0.0108 mole) were mixed together, and the resulting mixture was heated under reflux for a period of approximately one and one-half hours. At the end of this period, the normality of the reaction solution was adjusted to approximately 1 by the addition of hydrochloric acid, and the acidified solution was heated on the steam bath for a period of about fifteen minutes. The resulting solution was cooled and extracted with chloroform. The chloroform extract was evaporated to dryness, and the residual material was purified by recrystallization from ethanol to give substantially pure 7-keto-4b-methyl-1,2,3,4,4a,-

4b,5,6,7,9,10,10a-dodecahydrophenanthrene 1,4-

diol; M. P. 246 C.

Example 9 Ten cubic centimeters of absolute ethanol, 1.162 g. of 5-methyl-6-keto-perhydronapthalene- 1,4-dio1 (0.00586 mole), 1.3 cc. of a 50% aqueous solution of choline containing 0.71 g. of choline (0.00586 mole) and 1.45 cc. of an 85% aqueous solution of methyl vinyl ketone (0.0176 mole) were mixed together, and the resulting mixture was heated under reflux for a period of apwas purified abyrrrecrystallization; from ethanol to Various; changes and. modifications may i be;-

1,2;3,4,4a;4b,5,6,7;9,10,10a dodecahydrophenam:

threneelfl-diol which: comprises 5 bringing: into intimate contact; in; an alkaline reactions-medium; 5 methyi-6-ketoeperhydronaphthirlenedA 5- diol and methyl vinyl ketone;

3., The, process; which comprises. bringing together; in; an alkaline reaction medium-5.7.5-

methyl-S-keto-perhydronaphtha1ene -1, 4;"- diol; and a methyl B-substituted=ethyl ketone" compound characterized as. being decomposed by;- alkaline media with the; formation jfof' methyl vinyl ketone, thereby (producing; '7 -keto- 4b -.methe Insofar: asgthese changes and modifications yl-1,2,3,4,4a,4b,5',6,7,9,10,10a dodecahydrophen anthren'e-lA-diol;

V heating; the mixture thus formed thereby producing; 7-keto-4b-methyl-1,-2,3;4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene-1,i-diol.

5. The" process whichcomprises reacting 5- methyl-G-keto perhydronaphthalene 1,4 diol with" methyl vinyl ketone, said reaction being carried out-by heating the reactants together in an aqueous solution containing a quaternary ammonium hydroxide, thereby='producing. ,7-keto-.

4bsmethyl; 12,3,4,4a,4b,5,6;7,9,10,10a-dodecahydrophenanthrene-1,4-dio1'.

6. The process which comprises reacting 5e methyl-G-keto perhydronaphthalene 1,4 diol with N-(3-keto-butyl') N,N-diethyl N methylammonium iodide; said reaction being carried out by-zheating the reactants. together inan aqueous solution containing an-- alkali metal hydroxide, thereby producing 7-keto-4b-methyl-1,2,3,4,4a,- 4b,5;,6,7,9,10,10a-dodecahydrophenanthrene 1,4- diol.

LEWIS-'- H. SARE'I'I. ROGER -E. BEYLER.

Nosreferences cited. .e 

1. 7-KETO-4B-METHYL-1,2,3,4,4A,4B,5,6,7,9,10,10ADODECAHYDROPHENANTHRENE-1,4 -DIOL. 